Tandem transformations of 10-substituted tetrahydrobenzo[b][1,6] naphthyridines resulted from the Michael addition of the nitrogen atom of the tetrahydropyridine fragment to the triple bond of activated alkynes

Article abstract of DOI:10.1007/s11172-008-0200-y

A reaction of 10-R-substituted tetrahydrobenzo[b][1,6]naphthyridines (R = CN, CONH₂, Me) with dimethyl acetylenedicarboxylate, methyl and ethyl propiolates, and acetylacetylene has been studied. It was found that 1-acryloyl-10-cyanotetrahydrobe

Full text of DOI:10.1007/s11172-008-0200-y

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1547—1558, July, 2008
1547
Tandem transformations of 10ꢀsubstituted
tetrahydrobenzo[b][1,6]naphthyridines resulted from the Michael addition
of the nitrogen atom of the tetrahydropyridine fragment
to the triple bond of activated alkynes
L. G. Voskressensky, T. N. Borisova, I. V. Vorob´ev, N. M. Postika, E. A. Sorokina, and A. V. Varlamov
Peoples' Friendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (495) 955 0779. Eꢀmail: lvoskressensky@sci.pfu.edu.ru
A reaction of 10ꢀRꢀsubstituted tetrahydrobenzo[b][1,6]naphthyridines (R = CN, CONH2, Me)
with dimethyl acetylenedicarboxylate, methyl and ethyl propiolates, and acetylacetylene has been
studied. It was found that 1ꢀacryloylꢀ10ꢀcyanotetrahydrobenzo[b][1,6]naphthyridines are the major
products of the reaction of alkyl propiolates with 10ꢀcyanoꢀsubstituted naphthyridines, whereas
the reaction with 10ꢀcarbamoylꢀsubstituted naphthyridines gives a mixture of 1ꢀacryloylꢀsubstituted
naphthyridines and hexаhydrobenzo[b]pyrido[3,4,5ꢀd,e][1,6]naphthyridines. The latter are the only
products in the reaction of 10ꢀcarbamoylꢀsubstituted naphthyridines with acetylacetylene.
Key words: alkynes, the Michael reaction, benzo[b][1,6]naphthyridines, benzo[b]pyridoꢀ
[3,4,5ꢀd,e][1,6]naphthyridines.
Quinoline derivatives display a wide range of biologiꢀ
cal activity, some of them are used in medical practice.1
Quinolines are widely spread in the nature being a strucꢀ
tural fragment of the quinoline alkaloids family.2 For
a long time, quinolines served as the basis for the search
of synthetic antiꢀmalaria drugs. Therefore, the synthesis
of new quinoline derivatives or fused heterocyclic sysꢀ
tems containing quinoline fragment is an important synꢀ
thetic and practical problem. Recently, we developed
two approaches to the synthesis of pyrroloazocines and
azocinoindoles from tetrahydropyrrolo[3,2ꢀc]pyridines
and tetrahydroꢀγꢀ and ꢀβꢀcarbolines upon action of actiꢀ
vated alkynes. The first of them consists in the expansion
of the tetrahydropyridine ring in the indicated above hetꢀ
erocycles upon action of dimethyl acetylenedicarboxyꢀ
late (DMAD) or alkyl propiolates in aprotic solvents.3—5
This method gives rather low yield of fused azocines and
is limited in the type of substituents in the hydrogenated
ring; in addition, when methyl substituents are present in
the piperidine fragment, the process is complicated by
the formation of the Hofmann degradation products.6
The second approach is more general and promising and
consists in the tandem opening of the tetrahydropyridine
ring of the pyrrolopyridines and tetrahydrocarbolines with
alkynes in MeOH and cyclization of the thus formed
αꢀmethoxyalkylꢀβꢀalkoxycarbonylvinylaminoethylꢀsubꢀ
stituted pyrroles and indoles upon action of the Lewis
acids into pyrroloazocines and azocinoindoles.7 It was
found that the latter are able to efficiently inhibit acetylꢀ
and butyrylcholinesterases.8
It seemed reasonable to broaden this method to
10ꢀsubstituted tetrahydrobenzo[b][1,6]naphthyridines,
in which the tetrahydropyridine fragment is annulated
with the electronꢀwithꢀ
drawing quinoline. Reacꢀ
tions of compounds of
such a type with activated
alkynes have not been
studied. It would have
been interesting to examine the influence of electronic
effects of substituents on the reaction course and to obꢀ
tain new heterocyclic system, viz., tetrahydroazocinoquinꢀ
oline one.
However, the first experiments showed that tetraꢀ
hydrobenzo[b][1,6]naphthyridines react with alkynes
without opening and expansion of the tetrahydropyridine
ring.9,10 We conducted systematic research on the reacꢀ
tion of 10ꢀsubstituted tetrahydronaphthyridines 1—18
with DMAD, methyl and ethyl propiolates, and aceꢀ
tylacetylene, the results of which are reported in the preꢀ
sent work.
Results and Discussion
10ꢀCarbamoylꢀsubstituted naphthyridines 1—9 were
obtained by the Pfitzinger reaction from isatins and
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1516—1527, July, 2008.
1066ꢀ5285/08/5707ꢀ1547 © 2008 Springer Science+Business Media, Inc.

1548
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Voskressensky et al.
γꢀpiperidones in the presence of gaseous ammonia.11
Naphthyridines 1—7 upon action of POCl3 were convertꢀ
ed into 10ꢀcyanoꢀsubstituted naphthyridines 10—16. 10ꢀ
Methylꢀsubstituted naphthyridines 17 and 18 were synꢀ
thesized from 2ꢀaminoacetophenone and γꢀpiperidones
according to the known procedure.12
Cyanoꢀsubstituted naphthyridines 10, 11, 13, 15, and
16 readily react with DMAD and methyl propiolate
in MeOH, as well as with ethyl propiolate in ethanol
for 5—6 h at 20 °C. Acryloylꢀsubstituted naphthyꢀ
ridines 19—25 are the major products of the reaction
(Scheme 1). The reaction of naphthyridines 10 and 11
with DMAD, in addition to compounds 19 and 20, gives
also (1ꢀoxonaphthyridinꢀ10ꢀyl)methylenesuccinates 26
and 27.9
We assume that the reaction begins with the Michael
addition of the tertiary amine in benzonaphthyridines 10,
11, 13, 15, and 16 to the triple bond of the alkyne. The
intermediate zwitterion А is further transformed by two
pathways, A and B. Pathway A is conditioned by the acidic
character of the C(1)H2 group and leads to ylide B, which
by the Stevens rearrangement characteristic of ylides is
transformed into acryloylꢀsubstituted naphthyridines
19—25. The implementation of pathway B is caused by
the nucleophilic attack of the zwitterion at the nitrile
group. The intermediate C that formed through imine D
is converted into succinates 26 and 27 (see Scheme 1).
Comꢀ
pound
R
R´
R″
Comꢀ
pound
10
11
12
13
14
15
16
R
R´
R″
1
2
3
4
5
6
7
8
9
Me CONH2
Pri CONH2
Bn CONH2
Me CONH2
Pri CONH2
Me CONH2
Pri CONH2
H
H
H
Br
Br
F
Me
Pri
Bn
Me
Pri
Me
Pri
Me
Pri
CN
CN
CN
CN
CN
CN
CN
Me
Me
H
H
H
Br
Br
F
F
H
H
F
Me CONH2 NO2
Pri CONH2 NO2
17
18
Scheme 1
Compound
R
R″
H
H
H
H
X
CO2Me
CO2Me
H
Y
Compound
R
R″
Br
Br
F
X
H
H
H
Y
19
20
21
22
Me
Pri
Me
Pri
CO2Me
CO2Me
CO2Et
23
24
25
Me
Pri
Pri
CO2Et
CO2Et
CO2Me
H
CO2Et
R = Me (26), Pri (27)

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1549
The structures of compounds 25 and 26 unambiguously
were confirmed by the Xꢀray data.9
respectively. In the case of naphthyridine 2, Nꢀethoxyꢀ
carbonylvinylꢀsubstituted benzonaphthyridine 44, the
product of further vinylation of benzopyridonaphthyriꢀ
dine 31, was also isolated in small amount (6%).
Hexаhydrobenzo[b]pyrido[3,4,5ꢀd,e][1,6]naphthyridiꢀ
nes 34—37, which (excluding compound 37) are mixꢀ
tures of cisꢀ and transꢀisomers with respect to the posiꢀ
tion of protons H(3а) and H(3), were only isolated from
the reaction mixtures obtained in the reactions of naphꢀ
thyridines 1, 6, 7, and 9 with acetylacetylene. In the case
of naphthyridine 6, in addition to product 35, the product
of its further vinylation, viz, benzopyridonaphthyridine
45, was isolated in 12% yield.
The formation of mixtures of diаstereomers 34—36,
apparently, is defined by the higher electronegativity of
the acetyl group (in comparison with ester group), which
leads to the more planar anionic center in the original
zwitterion А and causes formation by protonation of inꢀ
termediate C with the transꢀ and cisꢀconfiguration of the
acrylate fragment.
It should be noted that in all the experiments, in
addition to compounds 19—25, colored crystalline comꢀ
pounds were isolated by chromatography in 2—5% yield,
the structures of which will be described in separate pubꢀ
lication.
Naphthyridines 12 (R = Bn, R″ = H) and 14 (R = Pri,
R″ = Br) do not react with DMAD in methanol at room
temperature. A reflux leads to elimination of benzyl or
isopropyl substituents and to formation of Nꢀdi(methoꢀ
xycarbonyl)vinylꢀsubstituted derivatives 28 and 29
(Scheme 2). Such an unusual behavior of compounds 12
and 14 requires additional studies.
Scheme 2
Naphthyridines 1, 2, 5—7, and 9 afforded only benꢀ
zopyridonaphthyridines 30—37 in 50—60% yield at
70 °C for 2.5 h.
The reaction of carbamoylnaphthyridines with alkꢀ
ynes begins also from the formation of zwitterion А
(see Scheme 3). The formation of ylide B and the Stevens
rearrangement lead to acryloylꢀsubstituted naphthyꢀ
ridines 38—43. The lower than in the case of 10ꢀcyanoꢀ
substituted naphthyridines СНꢀacidity of the C(1)H2
group conditions the pathway of transformations B, which
realizes through the formation of amideꢀanion С. The
addition of the latter to the double bond of the acrylate
fragment through the formation of zwitterion D and ylide
Е leads to the tetracyclic system of benzopyridonaphthyꢀ
ridines 30—37. The cisꢀposition of the protons in isoꢀ
mers of the type cisꢀ30—37 was confirmed by the Xꢀray
R″ = H (28), Br (29)
The Еꢀconfiguration of the double bond in butenoates
19, 20, 28, and 29 is ascribed on the basis of the literature
data.13
1
The carbamoyl group in position 10 of the naphꢀ
thyridines causes new directions in their tandem transꢀ
formations upon action of alkynes to appear. 10ꢀCarbꢀ
amoylnaphthyridines 1—9 are insoluble in methanol,
therefore, their reactions with activated alkynes were
studied in a DMF—methanol mixture (5 : 1, v/v) at
50 °C. Naphthyridines 1—9 turned out to be inactive in
the reaction with DMAD. After prolonged heating, only
small amounts of the tarꢀlike products were formed,
while compounds 1—9 were recovered from the reaction
mainly unchanged. Conversely, the terminal alkynes such
as alkyl propiolates and acetylacetylene readily reacted
with naphthyridines 1—9 under the conditions indicated
above (Scheme 3). Naphthyridines 1, 2, 5, and 9 upon
action of ethyl and methyl propiolates for 1 h produce
a mixture of cisꢀhexаhydrobenzo[b]pyrido[3,4,5ꢀd,e]ꢀ
[1,6]naphthyridines cisꢀ30—33 (see Ref. 10), and transꢀacꢀ
ryloylnaphthyridines transꢀ38—40 and transꢀ43. Naphꢀ
thyridines 4 and 7 afforded only acrylates 41 and 42,
data.10 In the Н and 13С NMR spectra of benzopyriꢀ
donaphthyridines 30—33, only one set of signals for each
proton and carbon atom in the molecule is present. The
signals for the protons H(3) and H(3a) are in the region δ
4.30—4.33 and overlap with the signals for other proꢀ
tons, which makes measuring of the spinꢀspin coupling
constants difficult. However, in the 1Н NMR spectrum of
compound 30, a doublet for the proton H(3a) at δ 3.87
with J3,3а = 5.4 Hz can be observed.
In the mixtures of diаstereomers 34—36, apparently,
the isomer with the cisꢀposition of the protons H(3) and
H(3a) is predominant (the ratio is (3 : 1)—(4 : 1)). We
1
made this conclusion on the basis of the Н NMR specꢀ
trum of a mixture of diаstereomers 34, where the signals
for the protons Н(3) (δ 4.35 (major) and δ 4.17 (minor)
and Н(3а) (δ 4.03 (minor), J3,3a = 11.0 Hz and δ 3.79
(major), J3,3a = 5.4 Hz) were identified. In the spectra of
naphthyridines 35 and 36, the signals for the protons
Н(3) and Н(3а) are observed as overlapping multiplets

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Voskressensky et al.
Scheme 3
Comꢀ
pound
30
31
32
33
34
35
R
R″
Y
Comꢀ
pound
36
37
38
39
40
41
R
R″
Y
Comꢀ
pound
42
43
44
R
R″
Y
Me
Pri
H
H
Br
NO2
H
CO2Et
CO2Et
CO2Et
CO2Me
COMe
COMe
Pri
Pri
F
NO2
H
H
Br
Br
COMe
COMe
CO2Et
CO2Et
CO2Et
CO2Et
Pri
Pri
Pri
Me
F
NO2
H
CO2Me
CO2Me
CO2Et
Pri
Me
Pri
Pri
45
F
COMe
Me
Me
Pri
F
Me
1
in the region δ 4.31—4.44. According to the Н NMR
data, the acryloyl fragment in compounds 38—43 has the
transꢀconfiguration, which unambiguously follows from
the spinꢀspin coupling constant values for the olefin proꢀ
tons (J = 12.0—14.1 Hz).
the tetrahydropyridine fragment upon the action of methꢀ
oxide anion (Scheme 4).
Different directions of the reactions of 10ꢀsubstituted
naphthyridines with alkynes, apparently, are conditioned
by different acidity of the C(1)H2 group (fragment
ArCH2—N). Calculation of charges on the С(3) atom of
the 4ꢀsubstituted quinolines by the Pariser—Parr—Pople
method (Table 1) confirmed our suggestion. In the series
of 10ꢀCNꢀ, 10ꢀCONH2ꢀ and 10ꢀMeꢀsubstituted naphꢀ
thyridines, СНꢀacidity of the methylene group in the
fragment ArCH2—N decreases since the electron density
10ꢀMethylꢀsubstituted tetrahydrobenzonaphthyridiꢀ
nes 17 and 18 did not react as expected with activated
alkynes even under reflux in MeOH and MeCN. Only in
the case of compound 18, the reaction with ethyl propiꢀ
olate after prolonged reflux led to 2ꢀvinylquinoline 46 in
12% yield, the product of the Hofmann degradation of

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1551
Scheme 4
plates were used for thinꢀlayer chromatography (visualization with
iodine vapors). Alumina (Fluka, II degree of activity) or silica gel
(Merk (230—400)) were used for column chromatography.
2ꢀRꢀ1,2,3,4ꢀTetrahydrobenzo[b][1,6]naphthyridineꢀ10ꢀcarbꢀ
oxamides 1—9 (general procedure). A mixture of corresponding
isatin (68.0 mmol) and Nꢀmethylꢀ, Nꢀisopropylꢀ, or Nꢀbenzylpipꢀ
eridinꢀ4ꢀone (75.2 mmol) in ethylene glycol (200 mL) was heated
for 2—3 h at 95—100 °C passing through the reaction mixture a flow
of ammonia (TLC control). The reaction mixture was cooled and
poured in water (200 mL). The crystals formed were recrystallized
from ethanol. Physicoꢀchemical constants and 1Н NMR spectra of
naphthyridines 1, 2, and 5 were described earlier.10
2ꢀBenzylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyridineꢀ10ꢀ
carboxamide (3). The yield was 41%, white crystals, m.p. 181—183 °C.
Found (%): С, 75.53; Н, 6.23; N, 13.54. C20H19N3O. Calculatꢀ
ed (%): С, 75.69; Н, 6.03; N, 13.24. MS ESI, m/z: 318 [M + 1]+.
1H NMR (CDCl3), δ: 2.86 (t, 2 Н, С(4)Н2, J = 5.7 Hz); 3.12 (t, 2
Н, С(3)Н2, J = 5.7 Hz); 3.72 (s, 2 Н, С(1)Н2); 3.75 (s, 2 Н,
CH2Ph); 7.29—7.44 (m, 5 Н, Ph); 7.53 (m, 1 Н, Н(8)); 7.68
(m, 1 Н, Н(7)); 7.74 (d, 1 Н, Н(6), J = 8.3 Hz); 7.91 (d, 1 Н, Н(9),
J = 8.3 Hz); 7.95, 8.15 (both br.s, 1 Н each, CONH2).
on the С(3) atom increases. In substituted quinolines, the
introduction of electronꢀwithdrawing substituents
in position С(6) decreases the electron density on the
С(3) atom.
It was shown that annulation of the tetrahydropyriꢀ
dine ring with electronꢀwithdrawing heterocycle localiꢀ
zes a positive charge +δ1 on the С(1) atom. This causes
appearance of new (as compared to the tetrahydropyꢀ
ridines fused with the electronꢀdonating πꢀheterocycles)
transformation channels, the directions of which are deꢀ
fined by СНꢀacidity of the СН2—N group bonded to
the hetaryl fragment. A considerable delocalization of
the +δ1 charge decreases the reactivity of the С(1) atom
with respect to nucleophiles.
Experimental
Mass spectra were recorded on a Varian MAT XL 95 mass
spectrometer with direct inlet of a sample into the source of ions
(70 eV). Mass spectra ESI were obtained on a Agilent 1100 Series
LC/MSD Trap System VL mass spectrometer under conditions of
ionization by electron cloud. 1Н and 13С NMR spectra were
recorded on a Varian Unity 400 (400 and 100 MHz) in CDCl3 or
DMSO with the use of solvents as the internal standards. Silufol UVꢀ254
8ꢀBromoꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphꢀ
thyridineꢀ10ꢀcarboxamide (4). The yield was 50%, pale brown
crystals, m.p. 228—230 °C. Found (%): С, 52.67; Н, 4.12; N, 12.93.
C14H14BrN3O. Calculated (%): С, 52.50; Н, 4.38; N, 13.13. MS
ESI, m/z: 320 [M + 1]+. 1H NMR (CDCl3), δ: 2.41 (s, 3 Н, NMe);
2.78 (t, 2 Н, С(4)Н2, J = 6.0 Hz); 3.11 (t, 2 Н, С(3)Н2, J = 6.0 Hz);
Table 1. Calculation of electron density (q) on atoms С(2) and С(3) by the Pariser—Parr—Pople
method in 4ꢀR,6ꢀR´ꢀsubstituted quinolines
Quinoline
6ꢀR´
q
Quinoline
4ꢀR
q
4ꢀR
C(2)
C(3)
6ꢀR´
C(2)
C(3)
H
Me
CONH2
CN
NO2
H
H
H
H
H
0.126
0.132
0.116
0.121
0.124
–0.015
–0.134
–0.031
+0.053
+0.043
CONH2
CONH2
CN
Cl
NO2
Cl
0.103
0.135
0.097
0.140
–0.023
–0.020
+0.056
+0.060
CN
NO2

1552
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Voskressensky et al.
3.65 (s, 2 Н, С(1)Н2); 7.81—7.88 (m, 3 Н, Н(6), Н(7), Н(9)); 8.05,
8.25 (both br.s, 1 Н each, CONH2).
(CDCl3), δ: 1.20 (d, 6 Н, 2 Me, J = 6.6 Hz); 2.99 (t, 2 Н, С(4)Н2, J
= 5.9 Hz); 3.08 (m, 1 Н, СНMe2); 3.28 (t, 2 Н, С(3)Н2, J = 5.9 Hz);
4.12 (s, 2 Н, С(1)Н2); 7.65 (m, 1 Н, Н(8)); 7.77 (dd, 1 Н, Н(7), J =
9.0 Hz, J = 2.3 Hz); 8.06 (d, 1 Н, H(6), J = 9.0 Hz); 8.10 (dd, 1 Н,
Н(9), J = 9.0 Hz, J = 2.3 Hz).
2ꢀBenzylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyridine (12).
The yield was 72%, yellow crystals, m.p. 130—132 °С. Found (%):
С, 80.03; Н, 5.43; N, 14.20. C20H17N3. Calculated (%): С, 80.27;
Н, 5.69; N, 14.05. MS, m/z: 299 [M]+. 1H NMR (CDCl3), δ: 2.94
(t, 2 Н, С(4)Н2, J = 6.2 Hz); 3.26 (t, 2 Н, С(3)Н2, J = 6.2 Hz);
3.79 (s, 2 Н, С(1)Н2); 4.10 (s, 2 Н, CH2Ph); 7.03 (ddd, 1 Н, Н(7),
J = 1.6 Hz, J = 7.4 Hz, J = 8.7 Hz); 7.29—7.44 (m, 5 Н, Ph); 7.65
(ddd, 1 Н, Н(6), J = 1.6 Hz, J = 7.4 Hz, J = 8.7 Hz); 8.06 (m, 2 Н,
H(8), Н(9)).
8ꢀBromoꢀ10ꢀcyanoꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b]ꢀ
[1,6]naphthyridine (13). The yield was 32%, orange crystals, m.p.
168—170 °C. Found (%): С, 55.78; Н, 3.78; N, 14.05. C14H12BrN3.
Calculated (%): С, 55.63; Н, 3.97; N, 13.91. MS, m/z: 301 [M]+.
1H NMR (CDCl3), δ: 2.58 (s, 3 Н, NMe); 2.92 (t, 2 Н, С(4)Н2,
J = 6.1 Hz); 3.26 (t, 2 Н, С(3)Н2, J = 6.1 Hz); 3.93 (s, 2 Н,
С(1)Н2); 7.03 (dd, 1 Н, Н(7), J = 8.9 Hz, J = 1.9 Hz); 7.92 (d, 1 Н,
Н(6), J = 8.9 Hz); 8.24 (d, 1 Н, H(9), J = 1.9 Hz).
8ꢀBromoꢀ10ꢀcyanoꢀ2ꢀisopropylꢀ1,2,3,4ꢀtetrahydrobenzo[b]ꢀ
[1,6]naphthyridine (14). The yield was 35%, pale red crystals, m.p.
96—98 °C. Found (%): С, 58.07; Н, 5.01; N, 12.92. C16H16BrN3.
Calculated (%): С, 58.18; Н, 4.85; N, 12.73. MS, m/z: 329 [M]+.
1H NMR (CDCl3), δ: 1.19 (d, 6 Н, 2 Me, J = 6.6 Hz); 2.96 (t, 2 Н,
С(4)Н2, J = 6.0 Hz); 3.08 (m, 1 Н, СНMe2, J = 6.6 Hz); 3.10 (t, 2 Н,
С(3)Н2, J = 6.0 Hz); 4.10 (s, 2 Н, С(1)Н2); 7.80 (dd, 1 Н, Н(7),
J = 8.8 Hz, J = 2.0 Hz); 7.90 (d, 1 Н, H(6), J = 8.8 Hz); 8.24
(d, 1 Н, Н(9), J = 2.0 Hz).
8ꢀFluoroꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyꢀ
ridineꢀ10ꢀcarboxamide (6). The yield was 76%, pale brown crystals,
m.p. 236—238 °C. Found (%): С, 65.00; Н, 5.19; N, 16.53.
C14H14FN3O. Calculated (%): С, 64.86; Н, 5.41; N, 16.22. MS,
1
m/z: 259 [M]+. H NMR (CDCl3), δ: 2.40 (s, 3 Н, NMe); 2.77
(t, 2 Н, С(4)Н2, J = 5.9 Hz); 3.11 (t, 2 Н, С(3)Н2, J = 5.9 Hz); 3.64
(s, 2 Н, С(1)Н2); 7.38 (dt, 1 Н, Н(7), J = 2.8 Hz, J = 9.1 Hz); 7.63
(dd, 1 Н, Н(6), J= 2.9 Hz, J= 9.1 Hz); 7.98 (dd, 1 Н, Н(9), J= 5.8 Hz,
J = 9.1 Hz); 8.06, 8.27 (both br.s, 1 Н each, CONH2).
8ꢀFluoroꢀ2ꢀisopropylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphꢀ
thyridineꢀ10ꢀcarboxamide (7). The yield was 87%, pale brown
crystals, m.p. 248—250 °C. Found (%): С, 66.73; Н, 6.30; N, 14.70.
C16H18FN3O. Calculated (%): С, 66.90; Н, 6.27; N, 14.63. MS,
m/z: 287 [M]+. 1H NMR (CDCl3), δ: 1.06 (d, 6 Н, 2 Me, J= 6.0 Hz);
2.87 (t, 2 Н, С(4)Н2, J = 5.6 Hz); 2.94 (m, 1 Н, CHMe2); 3.08
(t, 2 Н, С(3)Н2, J = 5.6 Hz); 3.79 (s, 2 Н, С(1)Н2); 7.37 (dt, 1 Н,
Н(7), J = 2.6 Hz, J = 9.0 Hz); 7.64 (dd, 1 Н, Н(6), J = 2.6 Hz,
J = 9.0 Hz); 7.99 (dd, 1 Н, Н(9), J = 5.6 Hz, J = 9.0 Hz); 8.06,
8.26 (both br.s, 1 Н each, CONH2).
2ꢀMethylꢀ8ꢀnitroꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyriꢀ
dineꢀ10ꢀcarboxamide (8). The yield was 25%, reddish yellow crysꢀ
tals, m.p. 239—240 °C. Found (%): С, 59.02; Н, 4.87; N, 19.85.
C14H14N4O3. Calculated (%): С, 58.74; Н, 4.90; N, 19.58. MS ESI,
m/z: 287 [M + 1]+. 1H NMR (CDCl3), δ: 2.44 (s, 3 Н, NMe); 2.82
(t, 2 Н, С(4)Н2, J = 5.8 Hz); 3.19 (t, 2 Н, С(3)Н2, J = 5.8 Hz);
3.79 (s, 2 Н, С(1)Н2); 8.10 (d, 1 Н, Н(6), J = 9.2 Hz); 8.44 (dd,
1 Н, Н(7), J = 2.1 Hz, J = 9.2 Hz); 8.23, 8.37 (both br.s, 1 Н each,
CONH2); 8.63 (d, 1 Н, Н(9), J = 2.1 Hz).
2ꢀIsopropylꢀ8ꢀnitroꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyꢀ
ridineꢀ10ꢀcarboxamide (9). The yield was 43%, reddish yellow
crystals, m.p. 221—223 °C. Found (%): С, 60.94; Н, 5.97; N, 17.63.
C16H18N4O3. Calculated (%): С, 61.15; Н, 5.73; N, 17.83. MS
ESI, m/z: 315 [M + 1]+. 1H NMR (CDCl3), δ: 1.19 (d, 6 Н, 2 Me,
J = 6.5 Hz); 2.84 (t, 2 Н, С(4)Н2, J = 5.7 Hz); 3.11 (m, 1 Н,
CHMe2); 3.22 (t, 2 Н, С(3)Н2, J = 5.7 Hz); 3.83 (s, 2 Н, С(1)Н2);
8.15 (d, 1 Н, Н(6), J = 9.0 Hz); 8.26, 8.47 (both br.s, 1 Н each,
CONH2); 8.54 (dd, 1 Н, Н(7), J = 2.3 Hz, J = 9.0 Hz); 8.77
(d, 1 Н, Н(9), J = 2.3 Hz).
10ꢀCyanoꢀ8ꢀfluoroꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b]ꢀ
[1,6]naphthyridine (15). The yield was 65%, pale yellow crystals,
m.p. 127—129 °C. Found (%): С, 69.78; Н, 5.06; N, 17.56.
C14H12FN3. Calculated (%): С, 69.71; Н, 4.98; N, 17.43. MS,
1
m/z: 241 [M]+. H NMR (CDCl3), δ: 2.58 (s, 3 Н, NMe); 2.93
(t, 2 Н, С(4)Н2, J = 6.1 Hz); 3.29 (t, 2 Н, С(3)Н2, J = 6.1 Hz); 3.97
(s, 2 Н, С(1)Н2); 7.51 (dt, 1 Н, Н(7), J = 8.0 Hz, J = 2.6 Hz);
7.71 (dd, 1 Н, Н(6), J = 8.0 Hz, J = 2.6 Hz); 8.08 (d, 1 Н, H(9),
J = 2.6 Hz).
10ꢀCyanoꢀ2ꢀRꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyriꢀ
dines 10—16 (general procedure). A solution of carbamoylꢀsubꢀ
stituted naphthyridines 1—7 (6.5 mmol) in freshly distilled POCl3
(25 mL) was heated for 2—4 h adding triethylamine (1 mL) every
1 h. The reaction course was monitored by TLC. The reaction
mixture was poured in ice (100 g), neutralized with saturated aqueꢀ
ous soda, made basic with NaOH to рН 10, and extracted with ether
(3×70 mL). The extract was dried with magnesium sulfate. The
residue after evaporation of ether was crystallized from ethyl acetate.
10ꢀCyanoꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphꢀ
thyridine (10). The yield was 44%, pale yellow crystals, m.p.
153—155 °C. Found (%): С, 75.12; Н, 5.95; N, 19.00. C14H13N3.
Calculated (%): С, 75.34; Н, 5.83; N, 18.83. MS, m/z: 223 [M]+.
1H NMR (CDCl3), δ: 2.58 (s, 3 Н, NMe); 2.91 (t, 2 Н, С(4)Н2,
J = 5.9 Hz); 3.19 (t, 2 Н, С(3)Н2, J = 5.9 Hz); 3.97 (s, 2 Н,
С(1)Н2); 7.65 (m, 1 Н, Н(8)); 7.76 (m, 1 Н, Н(7)); 8.06 (d, 1 Н,
H(6), J = 8.9 Hz); 8.15 (d, 1 Н, Н(9), J = 8.9 Hz).
10ꢀCyanoꢀ8ꢀfluoroꢀ2ꢀisopropylꢀ1,2,3,4ꢀtetrahydrobenzo[b]ꢀ
[1,6]naphthyridine (16). The yield was 60%, pale brown crystals,
m.p. 93—95 °C. Found (%): С, 71.20; Н, 6.07; N, 15.70.
C16H16FN3. Calculated (%): С, 71.38; Н, 5.95; N, 15.61. MS,
m/z: 269 [M]+. 1H NMR (CDCl3), δ: 1.20 (d, 6 Н, 2 Me,
J = 6.6 Hz); 2.98 (t, 2 Н, С(4)Н2, J = 6.0 Hz); 3.06 (m, 1 Н,
СНMe2, J = 6.6 Hz); 3.24 (t, 2 Н, С(3)Н2, J = 6.0 Hz); 4.11
(s, 2 Н, С(1)Н2); 7.52 (dt, 1 Н, Н(7), J = 8.0 Hz, J = 2.6 Hz); 7.70
(dt, 1 Н, H(6), J= 8.0 Hz, J= 2.8 Hz); 8.05 (d, 1 Н, Н(9), J= 2.8 Hz).
10ꢀMethylꢀ2ꢀRꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyriꢀ
dines 17 and 18 (general procedure). A solution of оꢀaminoacetoꢀ
phenone (8.0 mmol) and Nꢀmethyl(isopropyl)piperidinꢀ4ꢀone
(10.1 mmol) in anhydrous ethanol (50 mL) was refluxed for 4—5 h
passing through it a flow of dry hydrogen chloride. The reaction
course was monitored by TLC. The reaction mixture was cooled.
The crystals formed were filtered off, dissolved in saturated aqueous
NaOH (10 mL), extracted with dichloromethane, and dried with
magnesium sulfate. The residue left after evaporation of dichloꢀ
romethane was purified on a column with alumina.
10ꢀCyanoꢀ2ꢀisopropylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphꢀ
thyridine (11). The yield was 82%, colorless crystals, m.p. 110—112 °C.
Found (%): С, 76.64; Н, 6.53; N, 16.55. C16H17N3. Calculatꢀ
ed (%): С, 76.49; Н, 6.77; N, 16.73. MS, m/z: 251 [M]+. 1H NMR
2,10ꢀDimethylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphthyridine
(17). The yield was 23%, pale yellow crystals, m.p. 98—100 °C.

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1553
Table 2. Yields, melting points, elemental analysis data, and mass spectra of naphthyridines 19—46
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
MS,
m/z ([M]+)
(%)
C
H
N
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
16
13
69
14
39
40
21
26
32
47
24
33
20
19
23
43
34
28
12
28
32
40
40
39
22
5
157—158
135—137
148—150
111—113
152—154
102—103
135—137
235—236
205—206
182—184
204—206
172—173
118—120
219—220
201—203
171—173
167—169
192—194
224—226
205—207
143—145
103—105
121—123
152—154
213—215
118—120
189—191
137—139
65.75
65.50
67.35
67.18
70.89
71.01
73.98
73.90
56.81
57.00
58.53
58.80
67.83
68.00
62.51
62.66
64.35
64.23
64.91
64.96
53.18
53.02
67.41
67.26
68.51
68.66
56.28
56.50
60.51
60.30
69.78
69.90
65.90
66.06
67.35
67.60
62.58
62.83
67.48
67.26
68.50
68.66
56.48
56.50
54.33
54.55
62.85
62.97
58.53
58.38
67.32
67.10
66.70
66.84
74.32
74.56
5.22
5.30
5.90
5.85
5.80
5.96
4.90
5.11
4.71
4.50
5.00
5.14
5.84
5.67
5.70
5.48
5.80
6.08
4.90
4.84
4.89
4.72
5.95
6.19
6.90
6.81
5.54
5.38
5.36
5.53
6.27
6.15
5.72
5.50
6.38
6.20
5.83
5.76
6.25
6.19
6.90
6.81
5.25
5.38
5.00
4.78
5.32
5.25
5.00
4.86
6.75
6.67
5.38
5.57
7.51
7.69
11.61
11.50
10.75
10.69
13.20
13.08
12.15
12.03
10.32
10.50
10.05
9.81
12.00
11.90
12.58
12.73
10.45
10.22
12.03
11.97
9.81
С20Н19N3O3
С22Н23N3O3
С19Н19N3O2
С21Н23N3O2
С19Н18BrN3O2
С21Н22BrN3O2
С20Н20FN3O2
С20Н21N3O5
С22Н25N3O5
С19Н17N3O4
С19Н16BrN3O4
С19Н21BrN3O3
С21Н25N3O3
С21Н24BrN3O3
С20Н22N4O5
С18Н19N3O2
С18Н18FN3O2
С20Н22FN3O2
С20Н22N4O4
С19Н21N3O3
С21Н25FN3O3
С21Н24BrN3O3
С19Н20BrN3O3
С18Н18FN3O3
С18Н18N4O5
C26H31N3O5
С22Н21FN3O3
С21Н26N2O2
365
393
321
363
399*
427*
353
383
411
351
430*
339
367
445*
398
309
327
355
382
339
367
445*
417*
343
370
465
395
338
9.77
12.53
12.39
11.32
11.44
9.35
9.42
14.21
14.07
13.32
13.59
12.70
12.84
11.67
11.83
14.58
14.66
12.18
12.39
11.57
11.44
9.50
9.42
9.87
10.05
12.38
12.24
15.23
15.12
8.93
9.03
12
12
10.75
10.63
8.32
8.28
* For 79Br.

1554
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Voskressensky et al.

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1555

1556
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Voskressensky et al.

Benzo[b][1,6]naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1557

1558
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Voskressensky et al.
Found (%): С, 79.15; Н, 7.67; N, 13.03. C14H16N2. Calculatꢀ
ed (%): С, 79.25; Н, 7.55; N, 13.21. MS, m/z: 212 [M]+. 1H NMR
(CDCl3), δ: 2.52 (s, 3 Н, NMe); 2.57 (s, 3 Н, 10ꢀMe); 2.87 (t, 2 Н,
С(4)Н2, J = 5.9 Hz); 3.30 (t, 2 Н, С(3)Н2, J = 5.9 Hz); 3.76
(s, 2 Н, С(1)Н2); 7.46 (t, 1 Н, Н(7), J = 7.9 Hz); 7.68 (t, 1 Н, Н(8),
J = 7.9 Hz); 7.98 (d, 2 Н, H(6), Н(9)).
(d, 1 Н, N—CH=, J = 11.8 Hz); 7.60 (dd, 1 Н, Н(6), J = 8.4 Hz,
J = 7.3 Hz); 7.75 (dd, 1 Н, Н(7), J = 8.4 Hz, J = 7.3 Hz); 7.99
(d, 1 Н, Н(5), J = 8.4 Hz); 8.15 (d, 1 Н, Н(8), J = 7.3 Hz). MS, m/z
(Irel (%)): 338 [M]+ (3), 323 (5), 293 (15), 265 (15), 238 (100), 223
(20), 182 (56), 167 (42).
Authors are grateful to M. A. Ryabov for the calculaꢀ
tion of charges.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ32211).
2ꢀIsopropylꢀ10ꢀmethylꢀ1,2,3,4ꢀtetrahydrobenzo[b][1,6]naphꢀ
thyridine (18). The yield was 50%, pale brown crystals, m.p.
100—102 °C. Found (%): С, 79.73; Н, 8.20; N, 11.93. C16H20N2.
Calculated (%): С, 80.00; Н, 8.33; N, 11.67. MS, m/z: 240 [M]+.
1H NMR (CDCl3), δ: 1.21 (d, 6 Н, 2 Me, J = 6.5 Hz); 2.54 (s, 3 Н,
С(10)Н3); 2.91 (t, 2 Н, С(4)Н2, J = 5.7 Hz); 3.07 (sept, 1 Н,
СНMe2, J = 6.5 Hz); 3.22 (t, 2 Н, С(3)Н2, J = 5.7 Hz); 3.92
(s, 2 Н, С(1)Н2); 7.49 (t, 1 Н, Н(7), J = 8.1 Hz); 7.61 (t, 1 Н, H(8),
J = 8.1 Hz); 7.96 (d, 1 Н, Н(9), J = 8.1 Hz); 7.98 (d, 1 Н, Н(6)).
The reaction of 10ꢀcarbamoylꢀ and 10ꢀcyanotetrahydrobenꢀ
zo[b][1,6]naphthyridines with activated alkynes (general procedure).
Methyl and ethyl propiolates or acetylacetylene (2.5 mmol) were
added to a solution of 10ꢀcarbamoylnaphthyridines 1—9 (2.1 mmol)
in methanol—DMF (1 : 5) (20 mL) or 10ꢀcyanonaphthyridines
10—16 in anhydrous methanol (15 mL). The reaction mixture was
stirred for 2—12 h at room temperature. The reaction course was
monitored by TLC. The solvents were evaporated in vacuo. The
residue was chromatographed on alumina. Alkyl {[3S*,3aR*ꢀ4ꢀ
methyl(isopropyl)ꢀ1ꢀoxoꢀ2,3,3а,4,5,6ꢀhexаhydroꢀ1Нꢀbenzo[b]pyꢀ
rido[3,4,5ꢀd,e][1,6]naphthiridinꢀ3ꢀyl]}acetates 30—33 were eluted
first (ethyl acetate—hexane, 1 : 10) out of products of the reaction of
compounds 1—9 with alkyl propiolates, alkyl naphthiridylacrylates
38—43 were eluted second with hexane—ethyl acetate (2 : 1). In the
case of reaction with acetylacetylene, Nꢀmethoxycarbonylvinylꢀ
(oxopropenyl)benzopyridonaphthyridines 44 and 45 were eluted
first, whereas benzopyridonaphthyridines 34—37 were eluted second.
Alkyl (2Е)ꢀ3ꢀ[2ꢀmethyl(isopropyl)ꢀ10ꢀcyanoꢀ1,2,3,4ꢀtetraꢀ
hydrobenzo[b][1,6]naphthiridinꢀ1ꢀyl]acrylates 21—25 were obꢀ
tained from compounds 10—16. The reaction mixture of naphthyꢀ
ridines 10 and 11 with DMAD, after evaporation of methanol, was
chromatographed on alumina (ethyl acetate—hexane, 1 : 2) succesꢀ
sively eluting enedioates 19 and 20 and methylenesuccinates 26 and
27. Dimethyl 2ꢀ(1,6ꢀnaphthiridinꢀ2ꢀyl)butꢀ2ꢀenedioates 28 and
29 precipitated from the reaction mixture on cooling. The yields and
physicoꢀchemical constants of compounds synthesized are given in
Table 2, 1Н NMR spectroscopic data in Tables 3 and 4.
References
1. M. D. Mashkovskii, Lekarstva XX veka [Medicines of the 20th
Century], Novaya Volna, Moscow, 1998, 320 pp. (in Russian).
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kaloids, Ed. R. H. F. Manske, Academic Press, New York—Lonꢀ
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Chernyshev, A. V. Varlamov, Izv. Akad. Nauk, Ser. Khim.,
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mana, A. I. Chernyshev, Heterocycl. Commun., 2001, 7, 461.
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Kulikova, R. S. Borisov, A. V. Varlamov, Lett. Org. Chem.,
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Vorobiev, G. G. Alexandrov, A. V. Varlamov, J. Heterocycl.
Chem., 2005, 42, 1207.
Ethyl (Е)ꢀ3ꢀ{NꢀisopropylꢀNꢀ[(4ꢀmethylꢀ2ꢀvinylquinolinꢀ3ꢀ
yl)methyl]amino}acrylate (46). A solution of 10ꢀmethylnaphthyriꢀ
dine 18 (0.5 g, 0.2 mmol) and ethyl propiolate (0.29 g, 0.3 mmol) in
anhydrous methanol (30 mL) was refluxed for 25 h. The solvent was
evaporated in vacuo. The residue was chromatographed on alumina
(ethyl acetate—hexane, 1 : 10) to give acrylate 46 (40 mg, 6%).
Physicoꢀchemical constants and elemental analysis data are given in
Table 2. 1Н NMR, δ: 1.08—1.14 (m, 9 Н, MeCH2, Me2CH); 2.64
(s, 3 H, 4ꢀMe); 3.21 (m, 1 Н, CHMe2); 3.97 (q, 2 H, CH2Me);
4.57 (s, 2 H, NCH2); 4.91 (d, 1 Н, СН=, J = 11.8 Hz); 5.58 (dd, 1 Н,
СН2=, J = 10.6 Hz, J = 2.4 Hz); 6.50 (dd, 1 Н, СН2=, J = 16.6 Hz,
J = 2.4 Hz); 7.03 (dd, 1 Н, СН=, J = 10.6 Hz, J = 16.6 Hz); 7.34
11. F. Catto, M. Rosariadel Guidice, C. Mustazza, J. Heterocycl.
Chem., 1996, 33, 1807.
12. H. Oka, M. Iida, J. Sato, M. Hondа, Pat. USA 6.294.547;
Chem. Abstrs, 1999, 130, 110251.
13. T. N. Borisova, L. G. Voskressensky, T. A. Soklakova, L. N.
Kulikova, A. V. Varlamov, Mol. Diversity, 2003, 6, 202.
Received October 17, 2007;
in revised form March 28, 2008